JP2009502846A - GSK-3 inhibitor - Google Patents

Abstract

  The present invention relates to urea derivatives of formula (I) as inhibitors of glycogenase kinase 3β, GSK-3, processes for the preparation of these compounds, pharmaceutical compositions containing these compounds, and GSK- 3 for the treatment or prevention of diseases involving 3 (eg Alzheimer's disease or non-insulin dependent diabetes mellitus).

Description

Field of Invention

  The present invention relates to enzyme inhibitors, and more particularly glycogenogenic enzyme kinase 3β, urea derivatives as inhibitors of GSK-3, methods for producing such compounds, pharmaceutical compositions comprising these compounds, And their use for the treatment or prevention of diseases involving GSK-3, such as Alzheimer's disease or non-insulin dependent diabetes.

Background of the Invention

  In recent years, research on new therapeutic agents has been greatly accelerated as the structure of enzymes and other biomolecules associated with targeted diseases is better understood. One important enzyme class that has been the subject of extensive research is protein kinases. Many diseases are associated with abnormal cellular responses caused by protein kinase-mediated results. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone related diseases. Therefore, in pharmaceutical chemistry, intensive studies have been conducted to discover protein kinase inhibitors effective as therapeutic agents.

Glycogenase kinase-3 (GSK-3) is a serine / threonine protein kinase containing α and β isoforms, each encoded by a separate gene (Coghlan et al., Chemistry & Biology, 7, 793-803 ( 2000), Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)). Threonine / serine kinase glycogenase kinase-3 (GSK-3) plays a pivotal role in signal transduction pathways linked to various receptors (Doble, BW, Woodgett, JR J, Cell Sci, 2003, 116). : 1175-1186). Dysregulation in these pathways has been associated with a wide range of human diseases such as type II diabetes (Kaidanovich O, Eldar-Finkelman H, Expert Opin. Ther. Targets, 2002, 6: 555-561), Alzheimer's disease (Grimes CA, Jope). RS, Prog. Neurobiol, 2001, 65: 391-426), CNS abnormalities such as manic depression and neurodegenerative diseases, and chronic inflammatory disorders (Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett J, Nature 2000, 406: 86-90) is considered a serious consequence of the progression. These diseases can be caused by or can cause the abnormal operation of certain cell signaling pathways involving GSK-3.

GSK-3 is known to phosphorylate and regulate the activity of many regulatory proteins. These proteins include glycogen-producing enzyme, a rate-limiting enzyme required for glycogen production, protein Tau associated with microtubules, gene transcription factor β-catenin, translation initiation factor e1F2B, and ATP citrate lyase, axin , Thermal shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. These various protein targets are related to GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.

Currently, inhibition of GSK-3 is to develop a new group of medicines for use in the treatment of diseases that have not been overcome, either by insulin mimicry, tau dephosphorylation and amyloid treatment, or by transcriptional regulation. It can be a useful strategy (Martinez A, Castro A, Dorronsoro I, Alonso M, Med. Res. Rev., 2002, 22: 373-384).

As prior art, some compounds containing urea groups have already been disclosed as having GSK-3 inhibitory properties. For example, it is disclosed in International Publication Nos. WO03 / 004472, WO03 / 004475, and WO03 / 0889419. These publications disclose a large number of compounds defined by the Markush structure, which are large and complex, which makes the production of these compounds more complex and the compounds react. Increase the probability of In particular, these compounds have structural subgroups such as substituted thiazole compounds and heterocyclic amines. These compounds, among many other groups, can contain urea functional groups, among others. These compounds generally have an inhibitory effect on GSK-3 and thus have potential activity in the treatment and prevention of a range of diseases related to GSK-3, such as dementia, diabetes and mood disorders. It is said that. Nonetheless, none of the above references contain results on GSK-3 inhibition for certain compounds. Thus, no results have been shown to demonstrate the activity of urea derivatives for any of these compounds containing urea functional groups.

On the other hand, International Publication No. WO 03/004478 and the document “Structural Insights and Biological Effects of GSK-3 Specific Inhibitor AR-A014418”, J. Biol. Chem., 278 (46), 2003 includes one characteristic urea, 4- (4-methoxybenzyl) -N ′-(5-nitro-1,3-thiazol-2-yl). Urea has been described, which in fact has a much smaller and simpler structure than the urea described above. This urea has GSK-3 inhibitory properties and is therefore said to have potential activity to treat and / or prevent many symptoms associated with glycogenase kinase 3. Nevertheless, since the heterocyclic compound is described as having GSK-3 inhibitory properties, for example, as in the above-mentioned WO03 / 0889419, is this GSK-3 inhibitory effect due to urea itself? It is not clear whether it is due to nitro-thiazole.

Certain other ureas are disclosed for the treatment of neurological disorders, but with a completely different method of action, for example in WO 00/06156, in which urea is a glutamate receptor function. It is said to be a toughening agent.

Thus, there remains a need to find good GSK-3 inhibitors that are both effective and selective and have good “drug formation” properties, ie, good pharmaceutical properties with respect to administration, distribution, metabolism and excretion. It has been. It is also necessary to find compounds that have a simple and stable structure and can be easily prepared by routine procedures known to those skilled in the art.

Description of the invention

It has been found that a group of stable, small urea derivatives has an inhibitory effect on the GSK-3 enzyme.

（式中、
Ｒ_Ｂは、置換または未置換のアルキル、置換または未置換のシクロアルキル、アリールがフェニル、ナフチル、フェナントリルおよびアントラシルの群から選択される、置換または未置換のアリール、アラルキルがベンジルである、置換または未置換のアラルキル、アゼピン、ベンズイミダゾール、ベンゾチアゾール、フラン、イミダゾール、インドール、ピペリジン、ピペラジン、プリン、チアジアゾール、テトラヒドロフラン、ベンゾジオキソール、チオフェン、ベンゾフラン、インダゾール、キナゾリン、ピリダジン、ピリミジン、ピラジン、ピリジン、イソキサゾール、ピロール、ピラン、−ＯＲ_５、および−Ｓ（Ｏ）_ｔ−Ｒ_５から選択された複素環から選択されるものであり、Ｒ_Ｂは、Ｃ、Ｏ、ＮおよびＳから選択された８〜１５個の原子を含むが、但し、複素環によって置換された複素環ではなく、
Ｒ_３、Ｒ_４、Ｒ’_２、Ｒ’_３、Ｒ’_４、Ｒ’_５、およびＲ’_６は、それぞれ独立して、水素、置換または未置換のアルキル、置換または未置換のシクロアルキル、置換または未置換のアルケニル、置換または未置換のアリール、置換または未置換の複素環、−Ｃ（＝Ｏ）Ｒ_７、−Ｃ（＝Ｏ）ＯＲ_８、−Ｃ（＝Ｏ）ＮＲ_９Ｒ_１０、−Ｃ＝ＮＲ_１１、−ＣＮ、−ＯＲ_１２、−ＯＣ（＝Ｏ）Ｒ_１３、−Ｓ（Ｏ）_ｔ−Ｒ_１４、−ＮＲ_１５Ｒ_１６、−ＮＲ_１７Ｃ（＝Ｏ）Ｒ_１８、−ＮＯ_２、−Ｎ＝ＣＲ_１９Ｒ_２０またはハロゲンから選択されるが、その際、Ｒ_３およびＲ_４はともに＝Ｏ基を形成することができ、Ｒ_３Ｒ’_２、Ｒ_３Ｒ’_６、Ｒ_４Ｒ’_２、Ｒ_４Ｒ’_６、Ｒ’_２Ｒ’_３、Ｒ’_３Ｒ’_４、Ｒ’_４Ｒ’_５、Ｒ’_５Ｒ’_６、Ｒ_１５Ｒ_１６、Ｒ_１７Ｒ_１８またはＲ_１９Ｒ_２０のいずれの対も、ともに環状置換基を形成することができ、
ｔは０、１、２、３であり、
Ｒ_５は、水素、アルキル、アリールおよび複素環から選択されるものであり、
Ｒ_７、Ｒ_８、Ｒ_９、Ｒ_１０、Ｒ_１１、Ｒ_１２、Ｒ_１３、Ｒ_１４、Ｒ_１５、Ｒ_１６、Ｒ_１７、Ｒ_１８、Ｒ_１９およびＲ_２０は、それぞれ独立して、水素、置換または未置換のアルキル、置換または未置換のシクロアルキル、置換または未置換のアルケニル、置換または未置換のアリール、置換または未置換の複素環、置換または未置換されていないアルコキシ、置換または未置換のアリロキシ、ハロゲンから選択されるものである。）
で表される化合物、またはその、薬学的に許容され得る塩、プロドラッグまたは溶媒和化合物の、ＧＳＫ−３が仲介する病気または症状を処置および／または防止するための薬剤の製造における使用であり、前記病気または症状は、糖尿病、糖尿病に関連する症状、痴呆を包含する慢性神経変性症状、例えばアルツハイマー病、パーキンソン病、進行性核上性麻痺、亜急性硬化性全脳炎性パーキンソン症候群、脳炎後遺症パーキンソン症候群(postencephalitic parkinsonism)、ボクサー様(pugilistic)脳炎、グアムパーキンソン症候群−痴呆コンプレックス、ピック病、皮質基礎変性(corticobasal degeneration)、前頭側頭(frontotemporal)痴呆、ハンチントン病、ＡＩＤＳに関連する痴呆、筋萎縮性側索硬化症、多発性硬化症および神経外傷性の病気、例えば急性発作、てんかん、気分障害、例えばうつ病、精神分裂病および双極性障害、発作後の機能的回復促進、脳出血、例えば孤立性脳アミロイド脈管病によるもの、脱毛症、肥満症、高血圧、多嚢胞性卵巣症候群、Ｘ症候群、虚血、脳損傷、外傷性脳損傷、癌、白血球減少症、ダウン症候群、Lewy体疾病、炎症、慢性炎症性疾病、癌および過形成のような過増殖性疾病および免疫不全の群から選択される。 Formula (I) below:

(Where
R _B is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, aryl is selected from the group of phenyl, naphthyl, phenanthryl, and anthracyl, substituted or unsubstituted aryl, aralkyl is benzyl, substituted or Unsubstituted aralkyl, azepine, benzimidazole, benzothiazole, furan, imidazole, indole, piperidine, piperazine, purine, thiadiazole, tetrahydrofuran, benzodioxole, thiophene, benzofuran, indazole, quinazoline, pyridazine, pyrimidine, pyrazine, pyridine, Is selected from a heterocycle selected from isoxazole, pyrrole, pyran, —OR ₅ , and —S (O) _t —R ₅ , wherein R _B is selected from C, O, N and S ~ Containing 15 atoms, but not a heterocycle substituted by a heterocycle,
R ₃ , R ₄ , R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ , and R ′ ₆ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted _{heterocyclic, -C (= O) R 7} , -C (= O) oR 8, -C (= O) NR 9 R 10 , —C═NR ₁₁ , —CN, —OR ₁₂ , —OC (═O) R ₁₃ , —S (O) _t —R ₁₄ , —NR ₁₅ R ₁₆ , —NR ₁₇ C (═O) R ₁₈ , —NO ₂ , —N═CR ₁₉ R ₂₀ or halogen, wherein R ₃ and R ₄ together can form a ═O group, R ₃ R ′ ₂ , R ₃ R ′ _{6 , R 4 R '2, R} 4 R' 6, R '2 R' 3, R '3 R' 4, R '4 R' 5, R '5 _{'6, R} 15 any pair of _{R 16, R} 17 _{R 18} or _R 19 _{R 20} may, together can form a cyclic substituent,
t is 0, 1, 2, 3;
R ₅ is selected from hydrogen, alkyl, aryl and heterocycle;
R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ are each independently hydrogen, Substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy, substituted or unsubstituted Are selected from allyloxy and halogen. )
Or a pharmaceutically acceptable salt, prodrug or solvate thereof in the manufacture of a medicament for treating and / or preventing a disease or condition mediated by GSK-3. The disease or symptom is diabetes, diabetes-related symptoms, chronic neurodegenerative symptoms including dementia such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalic Parkinson's syndrome, encephalitis sequelae Parkinsonism (postencephalitic parkinsonism), boxer-like encephalitis, Guam Parkinson syndrome-dementia complex, Pick disease, corticobasal degeneration, frontotemporal dementia, Huntington's disease, AIDS related dementia, muscle Amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute seizures Epilepsy, mood disorders such as depression, schizophrenia and bipolar disorder, accelerated functional recovery after stroke, cerebral hemorrhage, eg due to isolated cerebral amyloid vascular disease, alopecia, obesity, hypertension, polycystic ovary Syndrome, syndrome X, ischemia, brain injury, traumatic brain injury, cancer, leukopenia, Down syndrome, Lewy body disease, inflammation, chronic inflammatory disease, hyperproliferative diseases such as cancer and hyperplasia and immunodeficiency Selected from the group of

A preferred compound is a compound in which R _B contains an aromatic group.

In a particular embodiment, R _B has at least 10 aromatic carbon atoms.

で表される化合物に関する。 In another aspect, the invention provides a compound of formula

It is related with the compound represented by these.

In another embodiment, the present invention provides a pharmaceutical comprising the compound of formula (I) above, or a pharmaceutically acceptable salt, prodrug or solvate thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. Relates to a functional composition.

Preferably, the disease or condition mediated by GSK-3 is selected from Alzheimer's disease, type II diabetes, depression and brain injury.

In another embodiment, the compound of formula (I) above can be used as a reactive substance for biological assays, preferably as a reactive substance for GSK-3 inhibition.

Detailed Description of the Invention

The urea derivative of formula (I) of the present invention is a chemical that surprisingly shows a good inhibitory effect on the GSK-3 enzyme, together with good stability and low toxicity.

As described above, in a first aspect, the present invention relates to a GSK-3 mediated disease or a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, It relates to the use in the manufacture of a medicament for treating symptoms. Preferably comprises R _B is an aromatic group, more preferably, R _B has at least 10 aromatic carbon atoms.

In a preferred embodiment, the compound of formula (I) has an aromatic group bonded directly to the N atom of the urea group.

In another particular embodiment, R _B is a substituted or unsubstituted naphthyl group, preferably an unsubstituted alpha-naphthyl group.

から選択される。 Preferably, R _B is

Selected from.

In a particularly preferred embodiment, R ₃ and R ₄ are H.

In another particular embodiment, R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ and R ′ ₆ are each independently hydrogen, substituted or unsubstituted alkyl, —C (═O ) R ₇ , —C (═O) OR ₈ , —OR ₁₂ , —NR ₁₅ R ₁₆ , or halogen, wherein R ₇ , R ₈ , R ₁₂ , R ₁₅ , and R ₁₆ are as defined above. Street.

Preferably, R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ and R ′ ₆ are H.

である。 Two preferred compounds of formula (I) are:

It is.

In the present invention, the description “GSK-3 mediated disease or condition” means any disease or other adverse symptom or condition in which GSK-3 plays a role. These diseases or symptoms include diabetes, diabetes related symptoms, chronic neurodegenerative symptoms including dementia such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalic Parkinson's syndrome, encephalitis sequelae Parkinson's syndrome, Boxer-like encephalitis, Guam Parkinson's syndrome-dementia complex, Pick's disease, cortical basic degeneration, frontotemporal dementia, Huntington's disease, AIDS related dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotrauma Sexual diseases such as acute seizures, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorder, functional recovery after seizures, cerebral hemorrhage, eg due to isolated cerebral amyloid vascular disease, alopecia, obesity Disease, hypertension, polycystic ovary syndrome, syndrome X, ischemia, brain injury, traumatic brain injury, cancer, leukopenia, da Down syndrome, Lewy body disease, inflammation, chronic inflammatory diseases, hyperproliferative diseases and immunodeficiency, such as cancer and hyperplasia, but not limited thereto.

Preferably, the disease or condition mediated by GSK-3 is Alzheimer's disease, type II diabetes, depression or brain injury.

In another aspect, the present invention relates to a compound represented by the following formula and use thereof as a medicament.

In another embodiment of the present invention, a pharmaceutical composition comprising a compound as described above, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The pharmaceutical composition is for oral administration. Preferred diseases or conditions that can be treated with this pharmaceutical composition include diabetes, diabetes-related symptoms, chronic neurodegenerative symptoms including dementia such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing all Encephalitic Parkinson's syndrome, encephalitis sequelae Parkinson's syndrome, boxer-like encephalitis, Guam Parkinson's syndrome-dementia complex, Pick's disease, cortical basic degeneration, frontotemporal dementia, Huntington's disease, AIDS related dementia, amyotrophic lateral sclerosis, Multiple sclerosis and neurotraumatic diseases such as acute seizures, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorder, accelerated functional recovery after stroke, cerebral hemorrhage such as isolated cerebral amyloid vascular disease Due to, alopecia, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischemia, brain injury, traumatic Injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, chronic inflammatory diseases, is a hyperproliferative diseases and immune deficiency, such as cancer and hyperplasia, but is not limited thereto.

Another aspect of the present invention is a method of treating or preventing a GSK-3 mediated disease or condition using a GSK-3 inhibitor, wherein the therapeutically effective amount for a patient in need thereof Administering a compound of formula (I) above or a pharmaceutical composition thereof.

In another aspect, the present invention is a method of inhibiting GSK-3 activity in a biological sample with a compound of formula (I), wherein the method comprises treating the biological sample with GSK-3 of formula (I). Contacting with an inhibitor. As used herein, the term “biological sample” includes cell cultures or extracts thereof, enzymes suitable for in vitro assays, biopsy material obtained from mammals or extracts thereof, and blood, saliva, urine, pharynx, There are, but are not limited to, semen, tears, or other body fluids or extracts thereof. For example, in one embodiment, the present invention relates to the use of a compound of formula (I) as a reactive substance for biological assays, in particular as a reactive substance for GSK-3 inhibition.

The definition of the compound of the above formula (I) means the following terms.

“Alkyl” is a straight or branched chain consisting of carbon and hydrogen atoms, not containing saturation, having 1 to 8 carbon atoms, attached to the rest of the molecule by a single bond. It means a hydrocarbon chain group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl and the like. The alkyl group may be optionally substituted by one or more substituents such as halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, and alkylthio.

“Alkoxy” means a group of the formula —OR _a where R _a is an alkyl group as defined above, eg, methoxy, ethoxy, propoxy, and the like.

“Alkoxycarbonyl” means a group of formula —C (O) OR _a where R _a is an alkyl group as defined above, eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and the like. .

“Alkylthio” means a group of the formula —SR _a where R _a is an alkyl group as defined above, eg, methylthio, ethylthio, propylthio, and the like.

“Amino” means a group of formula —NH ₂ , —NHR _a , or —NR _a R _b , where R _a and R _b are each independently an alkyl group as defined above. .)

“Aryl” is a phenyl, naphthyl, indenyl, phenanthryl, or anthracyl group, preferably phenyl or naphthyl. An aryl group optionally contains one or more substituents as defined herein (eg, hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl). ) May be substituted.

“Aralkyl” means an aryl group bonded to an alkyl group. Preferred examples include benzyl and phenethyl.

“Acyl” refers to the formulas —C (O) —R _c and —C (O) —R _d, where R _c is an alkyl group as defined above, and R _d is an aryl as defined above. Group), for example, acetyl, propionyl, benzoyl and the like.

“Aroylalkyl” means an alkyl group substituted with —R _a —C (O) —R _d , wherein R _a is an alkyl group as defined above, and R _d is the above An aryl group as defined in 1). A preferred example is benzoylmethyl.

“Carboxy” means a radical of the formula —C (O) OH.

"Cycloalkyl" means a stable 3-10 membered monocyclic or bicyclic group consisting solely of carbon and hydrogen atoms, saturated or partially saturated. Unless otherwise stated herein, the term “cycloalkyl” refers to cycloalkyl optionally substituted by one or more, eg, alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl. Meant to encompass groups.

“Halo” means bromo, chloro, iodo or fluoro.

“Heterocycle” means a heterocyclic group. The heterocycle is a stable 3 to 15 membered ring, preferably 1 to 5 containing 1 or more heteroatoms consisting of carbon atoms and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. An 8-membered ring, more preferably a 5- or 6-membered ring containing one or more heteroatoms is meant. For purposes of this invention, the heterocycle may be a monocyclic, bicyclic, or tricyclic system, and can include fused ring systems, where the nitrogen, carbon, or sulfur atom in the heterocyclic group is optionally oxidized. The nitrogen atom may be optionally quaternized and the heterocyclic group may be partially or fully saturated or aromatic. Examples of such heterocycles include azepine, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, thiadiazole, tetrahydrofuran, benzodioxole, thiophene, There are benzofuran, indazole, quinazoline, pyridazine, pyrimidine, pyrazine, pyridine, isoxazole, pyrrole, pyrazole, pyran.

As used herein, a substituted group in a compound of the invention means a specific group that may be substituted with one or more suitable groups at one or more substitutable positions. Suitable groups thereof include, for example, halogens such as fluoro, chloro, bromo and iodo, cyano, hydroxyl, nitro, azide, alkanoyl, C1-6 alkanoyl groups such as acyl, carboxamide, 1 to about 12 carbon atoms, Or alkyl groups, including groups having 1 to about 6 carbon atoms, more preferably 1 to 3 carbon atoms, one or more unsaturated bonds and 2 to about 12 carbon atoms or 2 to about 6 Alkenyl and alkynyl groups, including groups having one or more carbon atoms, one or more oxygen bonds and alkoxy groups having from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms, aryloxy such as phenoxy, one or more Alkylthios including thioether linkages and moieties having from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms An alkylsulfinyl group including one or more sulfinyl bonds and a moiety having 1 to about 12 carbon atoms or 1 to about 6 carbon atoms, one or more sulfonyl bonds and 1 to about 12 carbon atoms or 1 Alkylsulfonyl, aminoalkyl groups, including moieties having from about 6 carbon atoms, such as one or more N atoms and groups having 1 to about 12 carbon atoms or 1 to about 6 carbon atoms, substituted Unsubstituted cycloalkyl (cycloalkyl is as described above), unsubstituted aryl, especially phenyl or naphthyl, and aralkyl, such as benzyl. Unless otherwise specified, an optionally substituted group can have a substituent at each substitutable position of the group, and each substituent is independent of one another.

Unless otherwise specified, the compounds of the present invention include compounds that differ only in the presence of one or more isotope-rich atoms. For example, compounds having this structure also fall within the scope of the invention, except that hydrogen is replaced with deuterium or tritium, or carbon is replaced with 13C or 14C high carbon or 15N high nitrogen.

The term “pharmaceutically acceptable salt, derivative, solvate, prodrug” refers to any pharmaceutical agent that can be given (directly or indirectly) a compound described herein when administered to a patient. Means an acceptable salt, ester, solvate, or all other compounds. However, pharmaceutically unacceptable salts may also be useful in the preparation of pharmaceutically acceptable salts, and it goes without saying that these salts are also included within the scope of the present invention. Preparation of salts, prodrugs and derivatives can be carried out by methods known in the art.

For example, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In general, such salts are prepared, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or a mixture of both. Is done. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as acetate, maleic acid There are salts, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium salts, and organic alkali salts such as ethylenediamine, ethanolamine, N, N-dialkyleneethanolamine, triethanolamine. , Glucamine and basic amino acid salts.

Particularly preferred derivatives or prodrugs are biological compounds of such compounds when administered with a compound of the invention (eg, by making the orally administered compound more readily absorbed into the blood). A substance that increases availability or delivers a parent compound more strongly to a biological compartment (eg, the brain or lymphatic system) than the parent species.

All compounds that are prodrugs of compounds of formula (I) are included within the scope of the invention. The term “prodrug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives will be apparent to those skilled in the art and, depending on the functional groups present in the molecule, the following derivatives of this compound: esters, amino acid esters, phosphate esters, metal salt sulfonate esters, carbamates, and amides. However, it is not limited to these. Examples of methods for producing prodrugs of specific active compounds are known to those skilled in the art and are described, for example, in Krogsgaard-Larsen et al., “Textbook of Drugdesign and Discovery”, Tayloroe & Francis (April 2002). .

The compounds of the invention may be in crystalline form, as free compounds or as solvates (eg hydrates), both forms being included within the scope of the invention. Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.

The compounds of formula (I) or their salts or solvates are preferably pharmaceutically acceptable or in substantially pure form. Pharmaceutically acceptable forms have, inter alia, pharmaceutically acceptable levels of purity, exclude normal pharmaceutical additives such as diluents and carriers, and are toxic at normal dosage levels. Does not contain possible materials. The purity level for the drug substance is preferably greater than 50%, more preferably greater than 70%, and most preferably greater than 90%. In preferred embodiments, this level is greater than 95% of the compound of formula (I), or a salt, solvate or prodrug thereof.

The compounds of the present invention represented by the above formula (I) can include enantiomers depending on the presence of chiral centers or isomers depending on the presence of multiple bonds (eg, Z, E). Single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the invention.

The compounds of formula (I) as defined above can be synthesized according to the available synthetic procedures, for example in the following solvents, for example in N, N-dimethylformamide, dimethyl sulfoxide, dioxane, dichloromethane or tetrahydrofuran at +20 to + 150 ° C. It can be obtained by carrying out the reaction.

One preferred pharmaceutically acceptable form is the crystalline form, and in the case of salts and solvates encompassing such form in the pharmaceutical composition, the additional ionic system and solvent moiety are also non-toxic. There must be. The compounds of the present invention can have a variety of polymorphic forms, and the invention includes all such forms.

Examples of pharmaceutical compositions are all solids (tablets, pills, capsules, granules etc.) or liquid compositions (solutions, suspensions or emulsions) for oral, topical or parenteral administration.

In a preferred embodiment, the pharmaceutical composition is in oral form. Suitable dosage forms for oral administration are tablets and capsules, conventional additives known in the art such as binders such as syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone, fillers, For example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, tableting lubricants such as magnesium stearate, disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose, or pharmaceutically acceptable The resulting wetting agent may include, for example, sodium lauryl sulfate.

Solid oral compositions can be prepared by conventional methods of mixing, filling or tableting. Repeated mixing operations can be performed to distribute the active agent throughout these compositions using large amounts of filler. Such operations are common in the art. Tablets can be produced, for example, by wet or dry granulation and optionally coated with enteric coatings by methods well known in normal pharmaceutical practice.

This pharmaceutical composition can also be applied for parenteral administration, eg as a sterile solution, suspension or lyophilized product in a suitable unit dosage form. Suitable additives such as bulking agents, buffering agents or surfactants can be used.

The above formulations are prepared by standard methods, such as those described in Spanish and US Pharmacopeia and similar references.

Administration of the compounds or compositions of the invention can be performed by any suitable method, such as intravenous infusion, oral formulation, and intraperitoneal and intravenous administration. Oral administration is preferred because it favors the patient and the chronic nature of many diseases to be treated.

In general, the effective dosage of a compound of the invention will depend on the relative potency of the compound selected, the severity of the disorder being treated and the weight of the patient. However, the active compound is typically more than once a day, for example 1, 2, 3 or 4 times daily, with a typical total daily dose of 0.1 to 1000 mg / kg / day.

The compounds and compositions of the present invention can be used in combination with other drugs to provide combination therapy. Other drugs may form part of the same composition or be administered as separate compositions at the same time or at different times.

In the following, the present invention is further illustrated by examples. These examples do not limit the scope of the invention as defined in the claims.

Preparation of Compounds of Formula (II) The compounds of formula (II) of the present invention were prepared by reacting the appropriate isocyanate as described above with the appropriate amine to form the corresponding urea.

Example 1
Preparation of 1-benzyl-3-naphthalen-1-yl-urea 0.44 ml (4 mmol) of benzylamine was reacted with 0.58 ml (4 mmol) of 2-isocyanato-naphthalene in dichloromethane at room temperature overnight. Let

The resulting white precipitate is filtered and washed with diethyl ether. 1.18 grams of a white powder with a molecular weight of 276 are obtained. The corresponding 1H-NMR and 13C-NMR spectra are shown in FIG. These spectra indicate that the white compound is 1-benzyl-3-naphthalen-1-yl-urea.

Example 2
Preparation of 1-benzo [1,3] dioxol-5-yl-3-benzyl-urea 0.44 ml (4 mmol) of benzylamine was added to 654.5 mg of 5-isocyanato-benzo [1,3] dioxole ( 4 mmol) in dichloromethane at room temperature overnight.

The resulting white precipitate is filtered and washed with diethyl ether. 1 gram of white powder with a molecular weight of 276 is obtained. The corresponding 1H-NMR and 13C-NMR spectra are shown in FIG. These spectra indicate that the white compound is 1-benzyl-3-naphthalen-1-yl-urea.

Biological Methods GSK-3β Inhibition GSK-3β activity is achieved by culturing a mixture of recombinant human GSK-3 enzyme, phosphate source and GSK-3 substrate in the presence and absence of the corresponding test compound. It was determined by measuring the GSK-3 activity of this mixture.

  Recombinant human glycogen synthase kinase-3β was phospho-glycogen synthase peptide-2 (GS-2) 62.5 μM in MOPS 8 mM pH 7.3, EDTA 0.2 mM, MgCl 210 mM and sodium orthovanadate 0.25 mM. Assayed in the presence of 5 μCiγ-33P-ATP and unlabeled ATP final concentration of 12.5 μM. The final assay volume was 20 μl. After incubation at 30 ° C. for 30 minutes, 15 μl aliquots were spotted on P81 phosphocellulase paper. Filters were washed 4 times for at least 10 minutes each and counted in 1.5 ml of scintillation cocktail in a scintillation counter.

The values of GSK-3 activity in the presence of the compound of the present invention were measured at various concentrations, and the results of comparison with comparative samples are shown in FIGS.

IC50 values for these compounds were calculated by analyzing the inhibition curves by non-linear regression using GraphPad Prism. IC50 (concentration at 50% enzyme inhibition) values are shown in Table 1.

1H-NMR and 13C-NMR spectra of 1-benzyl-3-naphthalen-1-yl-urea are shown. 1H-NMR and 13C-NMR spectra of 1-benzo [1,3] dioxol-5-yl-3-benzyl-urea are shown. 2 is a graph showing the GSK-3 activity of 1-benzyl-3-naphthalen-1-yl-urea measured at various concentrations. These results are shown in comparison with a comparative sample. 1 is a graph showing GSK-3 activity of 1-benzo [1,3] dioxol-5-yl-3-benzyl-urea measured at various concentrations. These results are shown in comparison with a comparative sample.

Claims (21)

Formula (I) below:

(Where
R _B is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, aryl is selected from the group of phenyl, naphthyl, phenanthryl, and anthracyl, substituted or unsubstituted aryl, aralkyl is benzyl, substituted or Unsubstituted aralkyl, azepine, benzimidazole, benzothiazole, furan, imidazole, indole, piperidine, piperazine, purine, thiadiazole, tetrahydrofuran, benzodioxole, thiophene, benzofuran, indazole, quinazoline, pyridazine, pyrimidine, pyrazine, pyridine, Is selected from a heterocycle selected from isoxazole, pyrrole, pyran, —OR ₅ , and —S (O) _t —R ₅ , wherein R _B is selected from C, O, N and S ~ Containing 15 atoms, but not a heterocycle substituted by a heterocycle,
R ₃ , R ₄ , R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ , and R ′ ₆ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted _{heterocyclic, -C (= O) R 7} , -C (= O) oR 8, -C (= O) NR 9 R 10 , —C═NR ₁₁ , —CN, —OR ₁₂ , —OC (═O) R ₁₃ , —S (O) _t —R ₁₄ , —NR ₁₅ R ₁₆ , —NR ₁₇ C (═O) R ₁₈ , —NO ₂ , —N═CR ₁₉ R ₂₀ or halogen, wherein R ₃ and R ₄ together can form a ═O group, R ₃ R ′ ₂ , R ₃ R ′ _{6 , R 4 R '2, R} 4 R' 6, R '2 R' 3, R '3 R' 4, R '4 R' 5, R '5 _{'6, R} 15 any pair of _{R 16, R} 17 _{R 18} or _R 19 _{R 20} may, together can form a cyclic substituent,
t is 0, 1, 2, 3;
R ₅ is selected from hydrogen, alkyl, aryl and heterocycle;
R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ are each independently hydrogen, Substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy, substituted or unsubstituted Are selected from allyloxy and halogen. )
Or a pharmaceutically acceptable salt, prodrug or solvate thereof, diabetes, diabetes-related symptoms, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute Includes dementia such as sclerosing panencephalic Parkinson's syndrome, encephalitis sequelae Parkinson's syndrome, boxer-like encephalitis, Guam Parkinson's syndrome-dementia complex, Pick's disease, cortical basic degeneration, frontotemporal dementia, Huntington's disease, AIDS related to dementia Chronic neurodegenerative symptoms, amyotrophic lateral sclerosis, multiple sclerosis, and acute attacks, neurotraumatic diseases such as epilepsy, mood disorders such as depression, schizophrenia and bipolar disorder, post-stroke Functional recovery promotion, cerebral hemorrhage due to isolated cerebral amyloid vascular disease, alopecia, obesity, hypertension, polycystic ovary syndrome, X symptoms , Ischemia, brain injury, traumatic brain injury, cancer, leukopenia, Down syndrome, Lewy body disease, inflammation, chronic inflammatory diseases, hyperproliferative diseases such as cancer and hyperplasia, and immunodeficiency Use in the manufacture of a medicament for treating and / or preventing a GSK-3 mediated disease or condition selected from R _B comprises an aromatic group, Use according to claim 1. R _B has at least 10 aromatic carbon atoms Use according to claim 1.   Use according to claim 2, wherein the aromatic group is directly bonded to the N atom of the urea group. R _B is a substituted or unsubstituted naphthyl group, Use according to claim 3. R _B is an unsubstituted alpha - naphthyl group, Use according to claim 5. R _B is

The use according to claim 1, which is a group selected from: The use according to claim 1, wherein R ₃ and R ₄ are H. R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ and R ′ ₆ are each independently hydrogen, substituted or unsubstituted alkyl, —C (═O) R ₇ , —C (═O). OR ₈ , —OR ₁₂ , —NR ₁₅ R ₁₆ (wherein R ₇ , R ₈ , R ₁₂ , R ₁₅ , and R ₁₆ are as defined above), or selected from halogen The use according to claim 1, wherein _{R '2, R' 3,} R '4, R' 5 and R _'6 is H, Use according to claim 1. The compound of formula (I) is

The use according to claim 1, which is selected from:   The use according to claim 1, wherein the disease is Alzheimer's disease. The use according to claim 1, wherein the disease is type II diabetes.   The use according to claim 1, wherein the disease is depression.   The use according to claim 1, wherein the disease is brain injury. A compound represented by the following formula.

The compound used as a pharmaceutical represented by a following formula.

  A compound represented by the formula according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or A pharmaceutical composition comprising a vehicle.   19. A pharmaceutical composition according to claim 18 for oral administration.   Use of a compound of formula (I) according to any one of claims 1 to 11 as a reactive substance for biological assays, preferably as a reactive substance for inhibiting GSK-3 .   Diabetes, diabetes-related symptoms, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalic Parkinson's syndrome, encephalitis sequelae Parkinson's syndrome, boxer-like encephalitis, Guam Parkinson's syndrome-dementia complex, Pick's disease, Cortical basic degeneration, frontotemporal dementia, Huntington's disease, AIDS related to dementia, chronic neurodegenerative symptoms including dementia, amyotrophic lateral sclerosis, multiple sclerosis and nerves such as acute attacks, epilepsy Traumatic illness, mood disorders such as depression, schizophrenia and bipolar disorder, accelerated functional recovery after stroke, cerebral hemorrhage due to isolated cerebral amyloid vascular disease, alopecia, obesity, hypertension, polycystic Ovarian syndrome, syndrome X, ischemia, brain injury, traumatic brain injury, cancer, leukopenia, Down syndrome, Lewy body disease, inflammation, chronic inflammatory disease, A method of treating or preventing a GSK-3 mediated disease or condition selected from hyperproliferative diseases such as cancer and hyperplasia, and immunodeficiency with a GSK-3 inhibitor, which requires treatment 12. A method comprising administering to a patient having a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof according to any one of claims 1-11.

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